Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Tiedemann RE, Zhu YX, Schmidt J, Shi CX, Sereduk C, Yin H, et al. Identification of molecular vulnerabilities in human myeloma cells by RNAi lethality screening of the druggable genome. Cancer Res; Published OnlineFirst December 6, 2011; doi:10.1158/0008-5472. CAN-11-2781..Despite noteworthy progress in therapy for multiple myeloma, contemporary treatments are not curative. A factor frequently limiting efficacy is the toxicity of existing drugs. In this context, defining appropriate targets and novel therapeutic approaches is a mandatory step in the development of enhanced and selective molecular target–based therapy of malignant plasma cells. siRNA approaches have proved valuable in defining potentially important molecular targets controlling cellular physiology. This strategy has homed in on vital genetic elements that control tumor cell growth and survival. Tiedemann and colleagues conducted a genomescale lethality study with siRNAs in multiple myeloma. This strategy identified 160 lethal hits with 4 siRNAs per gene in 3 multiple myeloma cell lines and 2 nonmyeloma cell lines, culminating in the identification of 57 potent multiple myeloma survival genes. The most significant and selective multiple myeloma survival genes included MCL-1 and several 26S proteasome subunits. Additional relevant targets included genes associated with RNA splicing, ubiquitination, transcription, translation, and mitosis. Differentially expressed multiple myeloma survival genes in primary plasma cells compared with other human primary somatic tissue identified in this lethality screen included MCL1, TNK2, CDK11 and WBSCR22. The most striking differential functional susceptibility genes between multiple myeloma and non–multiple myeloma cells included the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5. Clearly, further evaluation is warranted of these genes as potential therapeutic targets in multiple myeloma.Ortiz-Zapater E, Pineda D, Martínez-Bosch N, Fernández-Miranda G, Iglesias M, Alameda F, et al. Key contribution of CPEB4-mediated translational control to cancer progression. Nat Med 2011 Dec 4. [Epub ahead of print].The contribution of alterations in gene expression at the translational level is an emerging area in cancer biology that is still poorly understood. Reprogramming of gene expression in cancer development has been extensively studied mainly at the level of transcription, which has produced many catalogs of mRNAs, but not proteins, altered in tumor cells. Intriguingly, Ortiz-Zapater and colleagues show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein known to mediate meiotic mRNA cytoplasmic polyadenylation and translational control, contributes to cancer progression and invasion by altering the translation of specific mRNAs. The authors show that the CPEB4 protein is overexpressed in pancreatic ductal adenocarcinoma as well as in glioblastomas in human tumors. They used a loss-of-function gene approach in vivo to show that reduced CPEB4 expression slows tumor growth and progression of pancreatic cancer associated with inhibition of cell proliferation and vascularization. Using RNA immunoprecipitation, the authors uncovered 842 mRNAs that were significantly associated with CPEB4 in pancreatic ductal adenocarcinoma. CPEB4 controls the posttranscriptional expression of these mRNAs by binding a consensus sequence, cytoplasmic polyadenylation element (CPE), located in their 3′ untranslated regions. The authors focused their functional validation on the tissue plasminogen activator (tPA) mRNA, which is translationally increased only in tumors when CPEB4 is overexpressed, but not in normal pancreatic tissues. Overexpression of tPA in xenografted cells depleted of CPEB4 resulted in an increased number of tumors. These exciting results support the important contribution of deregulations in translational control toward tumor growth and angiogenesis.Damsky WE, Curley DP, Santhanakrishnan M, Rosenbaum LE, Platt JT, Gould Rothberg BE, et al. β-Catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 2011;20:741–54.Metastatic disease is the leading cause of death in patients with melanoma. However, the molecular mechanisms as well as the changes in gene expression that lead to metastasis formation during melanoma progression are still poorly understood. Damsky and colleagues tackle this question with an elegant genetic approach. They use a conditional mouse model of melanoma based on melanocyte-specific Pten loss associated with activation of the Braf V600E mutation (Pten/Braf). Pten/Braf melanomas metastasize to lymph nodes with 100% penetrance. The authors use this faithful mouse model for human melanoma to unravel the role of Wnt signaling and β-catenin in regulation of metastasis. Genetic stabilization of β-catenin (Bcat-STA allele) in the Pten/Braf model accelerates tumor formation and increases the ability of melanoma cancer cells to disseminate to secondary sites such as lung and spleen. Interestingly, the Pten/Braf/Bcat-STA tumors were much more pigmented than the Pten/Braf tumors, and the authors provide strong evidence that this difference is associated with increases in melanocyte differentiation. Indeed, MITF, a transcription factor important for melanogenesis, was increased in Pten/Braf/Bcat-STA mice. These findings support the counterintuitive idea that ongoing differentiation in melanocytic tumors does not limit but instead increases metastatic potential. Damsky and colleagues further show that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling, as well as the Akt/mTOR pathway, is hyperactivated in Pten/Braf/Bcat-STA mice. Lastly, the authors show that human melanoma cell lines harboring loss of Pten, Braf mutations, and b-catenin stabilization exhibit the same alterations in gene expression observed in Pten/Braf/Bcat-STA derived tumors. These findings demonstrate that this mouse model faithfully recapitulates human melanoma. This article not only establishes a role for Wnt signaling in metastasis formation, but also provides important tools for future studies investigating melanoma therapies.Bhat KPL, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 2011;25:2594–609.Normal development requires cells to divide, with terminal differentiation leading to cessation of proliferation. The epithelialto-mesenchymal transition describes the proclivity for epithelial tissues to traverse backwards along this continuum, transitioning to a more mesenchymal stem-like tumor, and acquiring metastatic potential. Unlike epithelial tumors, these invasive gliomas are invasive from the start. Neither invasion nor metastases, in fact, are included in the grading system that distinguishes poor-prognosis, high-grade tumors from their low-grade counterparts with better prognosis. Nevertheless, more differentiated proneural subtypes of glioma are modestly less aggressive than mesenchymal subtypes and tend to recur as rapidly lethal malignancies, acquiring mesenchymal elements and undergoing a so-called proneural-tomesenchymal transition (PNT). Bhat and colleagues used gene network analyses of expression array data sets from the Cancer Genome Atlas, identifying TAZ, a transducer of the Hippo pathway known to induce stem-like properties in breast cancer, as enriched in mesenchymal subtypes of glioblastoma multiforme tumors. Additional studies using chromatin immunoprecipitation (ChIP) revealed that exogenously expressed TAZ was recruited directly to the promoters of mesenchymal genes, thereby driving their expression. Functionally, TAZ cooperated with platelet-derived growth factor (PDGF)-B to induce high-grade mesenchymal gliomas in a mouse model in which PDGF-B alone induced lowgrade, proneural tumors. These data reveal roles for TAZ and HIPPO signaling in driving PNT in malignant glioma.Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011;20:810–7.Although genetic heterogeneity is assumed to be common and widespread in most if not all tumors, our understanding of heterogeneity remains incomplete. In a recent article, Snuderl and colleagues provide a striking example of tumor heterogeneity in which multiple receptor tyrosine kinases (RTK) are amplified in independent subclones within single glioblastomas in a mosaic pattern. The authors studied 350 clinical cases and observed that 16 glioblastomas (4.5%) showed intermixed subclones with mutually exclusive EGFR, PDGFRA, and MET amplification. It was evident that these amplifications were not due to genome-wide instability, because each amplicon was revealed to be focal, based on array comparative genomic hybridization. The authors showed that subclones within a single tumor share early tumorigenic events such as homozygous deletion of CDKN2A or TP53 mutation and are thus derived from a common precursor. Furthermore, each amplification event resulted in overexpression of the corresponding protein, and each subclone was actively proliferating. The data suggest that each of the genetically defined subclones may occupy separate niches within the tumor microenvironment. The simultaneous amplification of multiple RTKs in different tumor cells may explain the lack of success with trials of targeted therapies in glioblastoma. Stable coexistence of multiple subclones may also play an important role during tumor progression, leading to collaboration among different subclones, rather than competition, which would have profound implications for future design of clinical trials targeting RTKs in these tumors.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.